In HIV-induced disease, the central nervous system (CNS) is both a target for virus infection as well as for damage induced by infection. Alcohol abuse is frequent among HIV-infected individuals and those at high risk for contracting HIV infection. Here we propose to examine the interactions of alcohol on the factors controlling SIV infection of the CNS of monkeys, as a model for ethanol effects on HIV in humans. Our working hypothesis is that the toxicity of HIV to the brain is initiated by viral infection of the brain, but is related more to the number and activation state of the brain microglia and macrophages, both of which increase following CNS virus infection. Does alcohol have an effect upon HIV entry and macrophage infiltration into the brain? This key question will be directly addressed here by these studies. This will be studied, in vivo, in the rhesus/SIV model. Events occurring during the acute phase after inoculation may greatly influence the disease induced by SIV. Since the CNS itself is both infected and affected early following inoculation, changes occurring during the acute infection period may dramatically alter CNS disease. Alcohol-treated and non-alcohol treated animals will be infected with SIV, and studied to determine the effect of ethanol on the initial course of SIV infection, and the effect of ethanol on SIV and macrophage entry into the CNS. We will examine the hypothesis that the CNS viral load and CNS macrophage infiltration resulting from SIV infection is altered by ethanol administration. There are numerous convergent processes that can be affected by alcohol and HIWSIV, such as effects on monocytic lineage cells, cytokines, chemokines, oxidative stress, viral infection and cell trafficking, that can result in untoward effects on the CNS. The mechanisms controlling CNS infection and macrophage infiltration will be investigated to pursue the nature of alcohol's effect.